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2012 Grants - Fossati

Death Receptors as Mediators of Amyloid-Induced Cerebrovascular Dysfunction

Silvia Fossati, Ph.D.
New York University School of Medicine
New York, New York

2012 New Investigator Research Grant

Alzheimer's disease often involves damage to the brain's blood vessels. The protein fragment beta-amyloid, a key suspect in Alzheimer's, can accumulate in and around such blood vessels. This pathology is called cerebral amyloid angiography (CAA), and it damages the vessel walls and leads to bleeding in the brain and possible cognitive decline. Yet the biological mechanisms that trigger CAA are poorly understood.

Sylvia Fossati, Ph.D., and colleagues have been studying CAA mechanisms using autopsied brain tissue from people with Alzheimer's. They have found that small beta-amyloid clumps called oligomers trigger a process that kills the cells on blood vessel walls. Specifically, oligomers appear to activate molecules on these cells called death receptors, which in turn signal enzymes (a protein that acts as a catalyst) known as caspases to carry out "apoptosis"—or programmed cell death. These findings identify death receptors as a novel therapeutic target for preventing brain damage caused by CAA.

For their proposed study, Dr. Fossati and colleagues will use cultured cells and autopsied brain tissue to verify their earlier results. They also hope to determine more precisely how the interaction of beta-amyloid oligomers and death receptors leads to blood vessel cell apoptosis. In addition, the researchers will test methods of hindering amyloid-induced death receptor activity. Such work could ultimately yield novel treatments for the cerebral bleeding and cognitive loss associated with dementia and CAA.